Some Success Stories

Two examples, among others, are illustrative of the way clinical science, diagnostic precision, and multinational networking can be combined to obtain therapeutic bene t: IPF and LAM. In IPF, the combination of an improved understanding of the disease pathogenesis, re ned consensus diagnostic criteria, and international multicenter collaboration has led to the worldwide approval of two drugs (nintedanib and pirfenidone) that are able to slow down functional decline and disease progression. These substantial advances represent new hopes for patients and a new vision of the disease for dedicated researchers and physicians. Similarly, a better understanding of the processes underpinning LAM [45] together with the emergence of a strong international network of clinicians-scientists and supported by a highly ef cient patient organization (see below) has resulted in the completion of a successful study of an agent, sirolimus, which was predicted to block the key pathogenetic mechanisms and indeed was found to lead to stabilization of lung function and improved quality of life [46, 47].

Both of these examples demonstrate that progress in the pathogenesis and treatment of rare diseases requires a team approach and an equipoise in collaboration that transcends individual interests to result in a successful outcome. These two examples may provide a template for other rare and orphan diseases that require the same sort of concerted organization that would attract research funding together with pharmaceutical company interest in developing focused therapies.

The Means to Overcome the Challenges of Clinical Research: Get Bigger Numbers of Well-Characterized Patients

One of the more fundamental obstacles to undertaking research in rare diseases is the absence of suf cient patient numbers to study disease causation, susceptibility, and phenotypes. Once these numbers are gathered, expertise and knowledge of the disease improve, patients become aware of research into their condition, and this becomes an iterative process of knowledge acquisition. An international survey conducted in 2018 by Rare Barometer Voices (a group of patients living with rare diseases and participating in EURORDIS studies) found that 64% of patients did not participate in any clinical trials for their condition [48]. Increasing patient numbers is the essential starting point, and there are a number of strategies that could be employed to facilitate this process.

The Importance of Patient Organizations

Patient organizations are vital in rare diseases as they form associations for patients to acquire better information, to become aware of the ways in which their disease might be managed, and to nd their way to experts who can offer therapy and guidance. In this manner, small numbers of individuals become larger cohorts who are generally all too willing to become participants in research studies. Patient advocacy organizations are valuable allies in the ght against rare dis-

eases as they provide education and support to patients and families. The LAM Foundation illustrates the impact of patient–parent advocacy groups on basic and clinical research into rare diseases. Until recently, a diagnosis of LAM has been a medical anomaly and a patient who received this diagnosis had little cause for hope due to both doctors being unfamiliar with the disease and the unavailability of effective drugs. The tremendous motivation of a mother of a young patient with LAM and the networking power of the Internet changed all this. Founded in 1995 and headquartered in Cincinnati, Ohio, the LAM Foundation has rapidly evolved into an organization described by the National Heart, Lung, and Blood Institute as “a model for voluntary health agencies.” The Foundation embraces women with LAM and their families, provides support and education, engages doctors and scientists, and raises funds for the study of LAM. The LAM Foundation has funded a number of studies that have dramatically improved our knowledge of the pathobiology of the disease [45], and we now know that LAM results from the aberrant proliferation of smooth muscle-like cells (“LAM cells”), which in ltrate organs, especially the lungs and the kidneys, via the blood and lymphatics [49, 50]. With an increasing understanding of the disease, clinical trials not only have become possible but also successful [46]. The LAM Foundation is a clear example of how advances can be made when patients, researchers, and funding bodies work together toward a common goal: the research community provides ideas and scienti c knowledge and patients contribute their personal insights, provide biological samples, and show dedication and courage as they put themselves at risk in clinical trials of potential treatments for their disease. In turn, the results of the clinical trials may lead to more focused basic research in what can be referred to as a “bench-to-­bedside-­ and-back” research strategy. Other organizations, including the Raynaud’s and Scleroderma Association in the UK and the Pulmonary Fibrosis Foundation in the United States, have similar templates that combine education, support, and research in their drive for better treatment for patients.

Patient organizations have also been a huge driving force in treatment development in cystic brosis and in neuromuscular disorders. An example of a successful clinical research network is the Cystic Fibrosis Therapeutics Development Network, an international network of about 50 centers formed by the Cystic Fibrosis Foundation in 1988. In just over a decade, this network has conducted more than 150 studies, involving hundreds of patients [51]. Finally, patient organizations are essential in order to identify speci c unmet medical needs, which, in turn, represent the main driver of research. In this regard, a study conducted by EURORDIS in 2009 showed that funding from patient organizations is mainly used to fund basic science, whereas public funding is mainly used for clinical, diagnostic, and therapeutic studies [52].

National and International Networks

Increasing the sample size of studies on rare diseases requires collaboration among research centers. This is essential in order to build up patient registries and databases, which, in turn, are vital to assess the feasibility and facilitate the planning of appropriate clinical trials and to support the enrollment of patients. In addition to building meticulous datasets, this approach would also serve to limit overlapping and competitive research efforts and avoid wasteful use of resources by replicating efforts that could have been more pro tably developed as collaborations. Rare disease research typically requires multiple sites to recruit suf cient numbers of participants. However, even when a disorder is clustered in speci c ethnicities or geographic areas, recruitment may be challenging. For instance, the prevalence of hereditary hemorrhagic telangiectasia is high (1/200) in Dutch Antilles owing to a founder effect. Nevertheless, recruitment from these islands has been limited by remote geography, patients’ fear of foreign medical institutions, and transportation costs. Ideally, registries and databases should be international, although there may be some heterogeneity in data sources and regulations across countries. For instance, alkaptonuria (AKU) is an ultra-rare autosomal recessive disorder characterized by high circulating levels of serum amyloid A and spondyloarthropathy, resulting in reduced quality of life. Cicaloni et al. developed an AKU-dedicated precision medicine “ecosystem” in which genetic, biochemical, and clinical resources can be shared among registered researchers [53]. One other approach would be to export the expertise rather than import the patients. With the widespread use of Internet and the explosion of social networks, it should not be long before research and even diagnoses can be developed remotely. Certainly, major international funding bodies need to invest in longer-term strategies at least at the pump-­priming stage. The practicalities should not be insurmountable. For the moment, where disease prevalence is such that it is often impossible to study large patient cohorts, trials can be designed using methodologies that allow ef cacy and safety to be balanced even with small patient numbers [54–58]. Such studies, provided they are well-designed, can result in regulatory approval despite their small size [59]. Further impetus could be provided by the creation of registries that would accurately capture the true prevalence and incidence of rare diseases across nations; this is not a trivial task as evidenced by the faws and dif culties observed in some of the existing registries. This requires signi cant resource to optimize the capture and audit of data. A second advance requires the continuing development of guidelines that would allow the harmonization of diagnostic criteria and management principles across nations [60, 61], as it has been done for IPF and LAM, for example.